The invention relates to a new process for the synthesis of 1 (aminomethyl)cyclohexyl-acetic acid of the formula (I) via the new intermediate 1-(nitromethyl)cyclohexyl-acetic acid compound of formula (II), wherein R represents hydrogen, benzyl group, diphenylmethyl group or C1-C4 alkyl or alkoxy aromatic ring substituted derivative thereof. 
The 1-(aminomethyl)cyclohexyl-acetic acid of formula (I), otherwise known as gabapentin is the active ingredient of the GABA antagonist drug. Several methods are known from the literature for the synthesis of this compound.
In most of the known methods an intermediate is hydrolyzed with acid, and gabapentin is obtained from the so formed gabapentin hydrochloride salt by using ion exchange resin. This process is described in the German patent No. DE 2 460 891, in which the 1,1-cyclohexyldiacetic acid anhydride is converted into hydroxamic acid and the latter is transformed via Lossen degradation into the hydrochloride salt of the product. The U.S. Pat. 4,024,175 describes a method where the same 1, 1-cyclohexyldiacetic acid anhydride is used as starting material. The anhydride is first transformed into a monoethyl ester monosalt and then a monoacid monoazide is obtained from it. The gabapentin hydrochloride is prepared from the latter via Curtius degradation.
Similarly gabapentin hydrochloride is formed in the procedure described in the European patent No. EP 414 274. According to this invention the alkyl ester of 1-(nitromethyl)acetic acid is transformed into a 2-aza-spiro[4,5]decane-3-on derivative by catalytic hydrogenation. The gabapentin hydrochloride is obtained from the latter lactam derivative by refluxing it with hydrochloric acid and gabapentin is isolated by using an ion exchange resin.
The disadvantages of the above mentioned procedures are as follows. The gabapentin is obtained as its hydrochloride salt and gabapentin itself can be isolated only by using labor-demanding and expensive ion-exchange methods. To avoid the unwanted lactam formation side-reaction requires also a labor-demanding and expensive technique. Further disadvantages of these procedures are the use of hazardous reagents, e.g. potassium cyanide, sodium azide and the expensive pressure resistant equipment. The procedure described in the European patent No. EP 414 275 avoids the formation of the lactam compound and the gabapentin hydrochloride, and in this way the use of the expensive ion-exchange method. According to this procedure cyano-cyclohexane-maleinic acid derivatives are hydrolyzed with base, decarboxylated and finally the nitrile group is catalytically hydrogenated. On the other hand this patent does not describe the synthesis of the cyano-cyclohexane-maleinic acid derivatives, which is a multi step, tedious process. It is important to note, that the synthesis of the maleinic acid ester is four steps starting from cyclohexanone, so the synthesis of gabapentin is altogether seven steps. The patent does not mention the purity of the obtained gabapentin either, in contrast to other patents, which describe the synthesis of gabapentin, e.g. EP 414 274.
The object of the invention is to elaborate an economical, industrially applicable process for the synthesis of gabapentin, which eliminates the disadvantages of the above mentioned procedures and makes possible the simple synthesis of the very pure final product of formula (I) in fewer steps and in good yield.
The synthesis of gabapentin according to the process of the invention is as follows
a) the alkyl ester of cyclohexylidene-acetic acid of general formula (VI)xe2x80x94wherein R2 represents C1-C4 alkyl groupxe2x80x94is transformed into the alkyl ester of 1-(nitromethyl) cyclohexyl-acetic acid of formula (V)xe2x80x94wherein the meaning of R2 is as defined abovexe2x80x94with nitromethane in the presence of a base, the latter is hydrolized with aqueous methanolic solution of potassium hydroxide and the obtained 1(nitromethyl)cyclohexyl-acetic acid of formula (Ila) is hydrogenated in a solvent in the presence of a catalyst to yield the desired product of formula (I), or 
b) the alkyl ester of cyclohexylidene-acetic acid of general formula (VI)xe2x80x94wherein the meaning of R2 is as defined abovexe2x80x94is hydrolyzed with aqueous methanolic solution of potassium hydroxide and the obtained cyclohexylidene-acetic acid of formula (IV) is reacted with a reagent of formula R1-Xxe2x80x94wherein R1 represents benzyl group, diphenylmethyl group or in given case C1-C4 alkyl or alkoxy aromatic ring substituted derivatives thereofxe2x80x94to give the appropriate cyclohexylidene acid derivative of the general formula (III)xe2x80x94wherein the meaning of R1 is as defined abovexe2x80x94and this intermediate is transformed into a 1-(nitromethyl)cyclohexyl-acetic acid compound of the formula (Ilb) wherein the meaning of R1 is as defined abovexe2x80x94with nitromethane and the latter is hydrogenated in a solvent in the presence of a catalyst. 
The process of the invention is illustrated on Scheme 1.
The invention based on the observation, that the reduction of the new compounds of the formula (II) at atmospheric pressure yields directly the pure desired final product.
Surprisingly it was found, that using the compounds of the formula (II) as starting materials in the reduction step the lactam compound is not formed, but the very pure gabapentin is obtained directly. This was not anticipated in the knowledge of previous procedures, as the ability of lactam formation of this type of compounds is known from the literature (e.g. EP 414 274).
The alkyl ester of cyclohexylideneacetic acid of the formula (VI) used as starting material can be prepared according to the literature via the reaction of cyclohexanone and the appropriate ester of diethylphosphono-acetic acid.
In the last hydrogenation step any catalysts can be used, which are generally applicable in hydrogenation reactions, rare metal catalysts, e.g. rhodium or palladium, Raney nickel or cobalt catalysts, in a given case on a carrier e.g. on carbon, preferably palladium on activated carbon, more preferably 10% of the compound to be reduced.
The hydrogenation is carried out in an inert organic solvent, preferably in a C1-C4 alcohol, more preferably in methanol, at 10-50xc2x0 C., under 1-20 kPa pressure, preferably at room temperature and under atmospheric pressure.
The Michael addition of the ester of cyclohexylidene-acetic acid with nitromethane is carried out in the presence of a base, preferably potassium hydroxide.
The hydrolysis of the alkyl ester group is carried out with base, preferably aqueous methanolic solution of potassium hydroxide at room temperature; then the acid is liberated with 10% aqueous potassium dihydrogenphosphate solution.
After filtration of the catalyst the product is isolated by concentration of the filtrate. The product obtained on concentration is 98-99% pure, the yield is 50-70%. The advantages of this procedure are as follows:
the obtained product is very pure
the number of reaction steps is less than in the known procedures
the lactam compound, which is very difficult to remove, is not formed
neither special pressure resistant equipment nor expensive catalyst is needed
the final product can be obtained without applying difficult and complicated ion-exchange technology
no poisonous or dangerous materials are needed